A 3-year-old boy is brought to the clinic due to fatigue. A few weeks ago, the patient's mother noticed that he seemed to tire easily after playing. He also appeared pale. The patient has had no recent illnesses and takes no medications. Temperature is 37 C (98.6 F). Examination shows mucosal pallor. The abdomen is soft with no organomegaly. The results of a complete blood count are as follows:
| Hemoglobin | 7.5 g/dL |
| Mean corpuscular volume | 66 µm3 |
| Red blood cell distribution width | 29% (normal: 11.8%-13.8%) |
| Platelets | 255,000/mm3 |
| Leukocytes | 6,800/mm3 |
Peripheral smear shows microcytic, hypochromic erythrocytes. The patient's condition does not respond to a trial of iron therapy. Further evaluation confirms the diagnosis, and the patient's symptoms improve with pyridoxine (vitamin B6). This patient most likely has an underlying impairment in which of the following reactions?
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This patient with microcytic anemia that improved with vitamin B6 (pyridoxine) but not iron supplementation likely has X-linked sideroblastic anemia (XLSA). XLSA is an X-linked recessive disorder affecting 5-aminolevulinate synthase. This enzyme, with vitamin B6 as a cofactor, catalyzes the first, rate-limiting step in porphyrin synthesis in which glycine and succinyl CoA form aminolevulinic acid.
Porphyrin combines with iron to form heme, which then combines with alpha- and beta-globin to form hemoglobin. In XLSA, impaired porphyrin synthesis leads to ineffective erythropoiesis as sufficient amounts of hemoglobin cannot be synthesized. As a result, patients develop microcytic anemia with an increased red blood cell distribution width and an inappropriately normal or low reticulocyte count. The anemia improves with vitamin B6 supplementation, which enhances the function of the defective 5-aminolevulinate synthase.
Vitamin B6 deficiency or isoniazid therapy (acts as a competitive inhibitor of vitamin B6) may induce sideroblastic anemia by impairing the function of 5-aminolevulinate synthase.
(Choices B through E) Vitamin B6 is not a cofactor for these enzymes, and anemia would not improve with vitamin B6 supplementation. However, other aberrations in the heme synthesis pathway cause clinically recognized disease. For example, porphyria cutanea tarda is an acquired condition in which the enzyme uroporphyrinogen decarboxylase (Choice D) is markedly inhibited, causing porphyrin accumulation in skin and photosensitivity. In addition, acute intermittent porphyria is an autosomal dominant disease in which porphobilinogen deaminase (Choice C) deficiency leads to episodes of abdominal pain and peripheral neuropathy.
Educational objective:
Vitamin B6 (pyridoxine) is a required cofactor for the enzyme 5-aminolevulinate synthase, which catalyzes the first, rate-limiting step in porphyrin synthesis. Defects in this enzyme cause X-linked sideroblastic anemia.